Uses for Antihemophilic Factor (Recombinant)

Hemophilia A

Prevention and control of hemorrhagic episodes in patients with a deficiency of coagulation factor VIII (antihemophilic factor) associated with hemophilia A (congenital factor VIII deficiency; classic hemophilia);1234592324404147485556686973747679114120121122126151 designated an orphan drug by FDA for this use.114

Because of a decreased risk of transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]) and other transmissible disease agents (e.g., agents for Creutzfeldt-Jakob disease [CJD], variant CJD [vCJD]) compared with plasma-derived antihemophilic factor (human), the National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) and other experts recommend antihemophilic factor (recombinant) as the preferred preparation when antihemophilic factor therapy is indicated in patients with hemophilia A.3489144049525569737679110 Recombinant and plasma-derived preparations of antihemophilic factor are similar and produce comparable hemostatic effects.3891440474849697376

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Antihemophilic factor replacement therapy generally is required in patients with mild to moderate hemophilia A who do not respond adequately to desmopressin or those with moderate to severe hemophilia A and factor VIII levels <5% of normal.566874799596126

Has been used for routine prophylaxis (i.e., administration at regular intervals) to prevent or reduce joint hemorrhage in individuals with severe hemophilia A.2120121126135136139140143151 Helixate FS and Kogenate FS are indicated for routine prophylaxis in children with no preexisting joint damage.120121 MASAC recommends prophylaxis in patients with severe hemophilia A (factor VIII activity <1%) after careful consideration of risks versus benefits.129

Hemophilia A with Inhibitors to Antihemophilic Factor

Prevention and treatment of bleeding in patients with hemophilia A who have developed relatively low levels of inhibitor antibodies (alloantibodies) to factor VIII.12275585120121122126142 (See Development of Inhibitors to Antihemophilic Factor under Cautions.) May be effective in those who are low responders and whose inhibitor levels have historically remained <5–10 Bethesda units/mL.26677477798595106120121122 Some manufacturers state that antihemophilic factor may be effective in patients with inhibitor levels ≤10 Bethesda units/mL;122 other clinicians recommend use of these preparations in those with inhibitor levels <5 Bethesda units/mL.126149150

Has been used to induce immune tolerance as a long-term strategy to eradicate or suppress further inhibitor production†.9599100101102106141 Such therapy eliminates risk of anamnesis with continued use of antihemophilic factor.9599100101102 While some experts state there is insufficient evidence to recommend use of immune tolerance therapy in patients with antihemophilic factor inhibitors, MASAC recommends such therapy for eradication of high-titer inhibitors.79

Generally should not be used for treatment of minor hemorrhage (e.g., cutaneous) in patients with inhibitors and a history of anamnestic response.95106108

Other therapeutic options for patients with inhibitors include bypassing agents such as anti-inhibitor coagulant complex (activated prothrombin complex concentrate [APCC]), factor VIIa (recombinant), or certain factor IX complex preparations (prothrombin complex concentrates [PCCs]).265561626773747778799597127128131141149 MASAC currently recommends use of a bypassing agent in hemophilia A patients with inhibitors to prevent or control bleeding in settings where antihemophilic factor preparations would otherwise be used, including before and after surgery and physical therapy.131

Management of hemophilia A in patients with inhibitors may be difficult and consultation with a hemophilia treatment center is strongly recommended.5574798595126

Acquired Hemophilia

Has been used to control bleeding in patients without hemophilia A who spontaneously acquire inhibitors (autoantibodies) to factor VIII.18593106 Autoantibodies are similar to but more heterogeneous than the alloantibodies that develop in patients with hemophilia A.2831556167889093

Keep reconstituted solutions at room temperature and administer within 3 hours after reconstitution.12121122151

The surfactant (polysorbate 80) contained in reconstituted Xyntha solutions is known to increase the rate of extraction of diethylhexylphthalate (DEHP) from PVC containers and administration sets.151 The manufacturer states that this should be considered during preparation and administration of the drug, including storage time elapsed in a PVC container following reconstitution.151

Rate of Administration

Individualize infusion rates according to patient response.12120121122151 Monitor pulse before and during infusion.1120121122 Slow infusion rate or temporarily discontinue therapy if there is a substantial increase in pulse rate.12120121122

Dosage

Dosage expressed in terms of international units (IU, units).12120121122151 One unit is approximately equivalent to amount of factor VIII activity in 1 mL of fresh pooled normal human plasma.7295120121122151

Use the following calculations and dosage guidelines (based on the degree of hemorrhage or type of surgery) for administering the drug.12106120121122151These calculations and suggested dosage regimens are only approximations and should not preclude appropriate clinical monitoring and laboratory determinations of factor VIII levels.1255120121122151Perform serial assays of factor VIII (e.g., with one-stage clotting assay) at suitable intervals when clinically indicated to ensure that adequate levels have been attained and maintained.12120121122 (See Laboratory Monitoring under Cautions.)

Careful control of the dose is especially important in cases of life-threatening bleeding or major surgery.1120121122 If recommended dosage is ineffective in achieving expected factor VIII levels or if bleeding is not controlled, consider the possibility that inhibitors to antihemophilic factor may have developed.1120121122 (See Development of Inhibitors to Antihemophilic Factor under Cautions.) Some patients with inhibitors (e.g., those with low-titer inhibitors) may require higher dosages.12120122151

Pediatric Patients

Hemophilia A

Advate

IV

Children ≤16 years of age with early hemarthrosis, mild muscle hemorrhage, or mild oral bleeding: Initially, 10–20 units/kg to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours (8–24 hours for patients <6 years of age) for 1–3 days until bleeding episode resolves (indicated by pain relief) or healing achieved.122

Children ≤16 years of age with moderate bleeding into muscles, bleeding into oral cavity, definite hemarthrosis, or known trauma: Initially, 15–30 units/kg to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours (8–24 hours for patients <6 years of age) for ≥3 days until bleeding episode resolves (indicated by pain relief) or healing achieved.122

Children ≤16 years of age with substantial GI bleeding; intracranial, intra-abdominal, or intrathoracic bleeding; CNS bleeding; bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath; fractures; or head trauma: Initially, 30–50 units/kg to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours (6–12 hours for patients <6 years of age) until bleeding episode resolves.122

Children ≤16 years of age undergoing minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal.122 Single bolus infusion of 30–50 units/kg is given within 1 hour of surgery.122 Infusions may be repeated every 12–24 hours as needed to control bleeding.122 Consider adjunctive therapy for dental procedures.122

Children ≤16 years of age undergoing major surgery (intracranial, intra-abdominal, or intrathoracic surgery; joint replacement): Initially, 40–60 units/kg to achieve pre- and postoperative factor VIII levels of 80–120% of normal (must verify 100% factor activity prior to surgery).122 Repeat dose every 8–24 hours (6–24 hours for patients <6 years of age) to desired factor VIII activity and state of wound healing.122

Helixate FS and Kogenate FS

IV

Children of any age with minor hemorrhage (e.g., early hemarthrosis, minor muscle or oral bleeding): Initially, 10–20 units/kg to achieve a plasma factor VIII level of 20–40% of normal; repeat if bleeding continues.120121

Children of any age with moderate hemorrhage (bleeding into muscles or oral cavity, definite hemarthroses, known trauma): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120121

Children of any age with majorhemorrhage (intracranial, intra-abdominal, or intrathoracic hemorrhages; GI bleeding; CNS bleeding; bleeding in retropharyngeal or retroperitoneal spaces or iliopsoas sheath), fractures, head trauma: Initially, 40–50 units/kg to achieve a plasma factor VIII level of 80–100% of normal; give additional doses of 20–25 units/kg every 8–12 hours until bleeding resolves.120121

Children of any age undergoing minor surgery (e.g., tooth extraction): Initially, 15–30 units/kg to achieve a plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours until bleeding resolves.120121

Children of any age undergoing major surgery (e.g., tonsillectomy, inguinal herniotomy, synovectomy, total knee replacement, craniotomy, osteosynthesis, trauma): Initially, 50 units/kg preoperatively to achieve a plasma factor VIII level of 100% of normal (must verify 100% factor activity prior to surgery); may repeat after 6–12 hours initially, and for 10–14 days until healing complete.120121

Recombinate

IV

Children of any age with early hemarthrosis, muscle hemorrhage, or oral bleeding: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours for 1–3 days until bleeding resolves (indicated by pain relief) or healing occurs.1

Children of any age with moreextensive hemarthrosis, muscle hemorrhage, or hematoma: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for ≥3 days until pain and disability resolve.1

Children of any age with life-threatening bleeding (e.g., head injury, throat bleeding, severe abdominal pain): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.1

Children of any age undergoing minor surgery (including tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–80% of normal.1 A single infusion in conjunction with oral antifibrinolytic therapy within 1 hour usually sufficient in about 70% of patients.1

Children of any age undergoing major surgery: Use appropriate dosage to achieve plasma pre- and postoperative factor VIII levels of 80–100% of normal.1 Repeat dose every 8–24 hours to desired factor VIII activity and state of wound healing.1

ReFacto and Xyntha

IV

Children of any age with minor hemorrhage (early hemarthrosis, minor muscle hemorrhage, oral bleeding): Use appropriate dosage to achieve a plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours as needed until bleeding resolves.2151 Give at least 1 day of therapy (depending on the severity of hemorrhage).2151

Children of any age with moderate hemorrhage (muscle hemorrhage, mild trauma capitis, hemorrhage into oral cavity): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; repeat infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2151

Children of any age with major hemorrhage (GI, intracranial, intra-abdominal, or intrathoracic hemorrhages) or fractures: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until bleeding resolves.2151

Children of any age undergoing minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; repeat infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2151 For tooth extraction, a single infusion in conjunction with oral antifibrinolytic therapy within 1 hour may be sufficient.2151

Children of any age undergoing major surgery: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis and/or wound healing is achieved.2151

Routine Prophylaxis

IV

Various dosing regimens have been recommended; optimal dosage remains to be established.120121126129136139 Dosages of 25–40 units/kg every other day (minimum 3 times a week) usually recommended.120121126136139151 MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% in between infusions.129136

Institute prophylactic therapy early (e.g., 1–2 years of age) prior to onset of frequent bleeding.129139

Evaluate patients periodically to determine continued need for prophylaxis.129

Minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–100% of normal within 1 hour of surgery.122 Single bolus infusion of 30–50 units/kg is given within 1 hour of surgery.122 Infusions may be repeated every 12–24 hours as needed to control bleeding.122 Consider adjunctive therapy for dental procedures.122

Recombinate

IV

Early hemarthrosis, muscle hemorrhage, or oral bleeding: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours for 1–3 days until bleeding resolves (indicated by pain relief) or healing occurs.1

Moreextensive hemarthrosis, muscle hemorrhage, or hematoma: Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 30–60% of normal; repeat every 12–24 hours for ≥3 days until pain and disability resolve.1

Minor surgery (including tooth extraction): Use appropriate dosage to achieve a peak postinfusion plasma factor VIII level of 60–80% of normal.1 A single infusion in conjunction with oral antifibrinolytic therapy within 1 hour usually sufficient in about 70% of patients.1

Major surgery: Use appropriate dosage to achieve pre- and postoperative plasma factor VIII levels of 80–100% of normal.1 Repeat dose every 8–24 hours to desired factor VIII level and state of wound healing.1

ReFacto and Xyntha

IV

Minor hemorrhage (early hemarthrosis, minor muscle hemorrhage, oral bleeding): Use appropriate dosage to achieve a plasma factor VIII level of 20–40% of normal; repeat every 12–24 hours until bleeding resolves.2151 Give at least 1 day of therapy (depending on the severity of hemorrhage).2151

Major hemorrhage (GI, intracranial, intra-abdominal, or intrathoracic hemorrhages), fractures: Use appropriate dosage to achieve a plasma factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis achieved.2151

Minor surgery (e.g., tooth extraction): Use appropriate dosage to achieve a plasma factor VIII level of 30–60% of normal; administer infusions every 12–24 hours for 3–4 days until local hemostasis achieved.2151 For tooth extraction, a single infusion in conjunction with oral antifibrinolytic therapy within 1 hour may be sufficient.2151

Major surgery: Use appropriate dosage to achieve a factor VIII level of 60–100% of normal; repeat every 8–24 hours until local hemostasis and wound healing achieved.2151

Routine Prophylaxis

IV

Various dosing regimens have been recommended; optimal dosage remains to be established.120121126129136139 Dosages of 25–40 units/kg every other day (minimum 3 times a week) usually recommended.120121126136139151 MASAC states that an antihemophilic factor dosage of 25–50 units/kg 3 times a week or every other day usually is sufficient to maintain trough factor VIII concentrations >1% in between infusions.129136

Evaluate patients periodically to determine continued need for prophylaxis.129

Although the manufacturer of Xyntha states that there are no known contraindications to use of the drug, patients receiving this drug may develop hypersensitivity to hamster protein, which is present in trace amounts in the preparation.151 (See Antibody Formation to Trace Animal Proteins under Cautions.)

Inhibitors usually identified in patients <20 years of age; those <10 years of age appear to be at greatest risk.2757585962639598104106 Probability of developing inhibitors is highest during the first 20 days of exposure to the drug.1106 Inhibitors more common in previously untreated patients, but also reported in previously treated patients.120121122151 Inhibitors may diminish or neutralize response to therapy.12142 Anamnestic response and increased levels of inhibitor possible with continued use of drug.1

Monitor for development of inhibitors during treatment with clinical observation and appropriate laboratory tests.122728556567749195120121122151 Perform quantitative test (e.g., Bethesda assay) for inhibitors routinely (e.g., every 3–6 months) and immediately prior to surgery.235556606674106126 The World Federation of Hemophilia recommends that children be screened every 3–12 months or every 10–20 days following drug exposure, whichever occurs first.126 Consider possibility that inhibitors may have developed in patients who fail to respond to adequate dosages of antihemophilic factor (recombinant) or those with unusually prolonged aPTT.12761657495120121122142151

Consider several factors (e.g., severity and location of bleeding, type [low- or high-responding] and titer of inhibitors, history of anamnestic antibody response, previous response to these preparations) when treating patients with inhibitors.26275562677477798595126127 Consultation with a hemophilia treatment center strongly recommended.79126 Carefully monitor such patients, especially when surgical procedures indicated.1556074798595126 Higher than recommended dosages may be required to achieve hemostasis in patients with inhibitors.12120121122151

Antibody Formation to Trace Animal Proteins

Some preparations of antihemophilic factor (recombinant) contain trace amounts of animal proteins (Advate, Helixate FS, Kogenate FS, Recombinate, ReFacto, Xyntha), which may stimulate antibody production and cause hypersensitivity reactions.12120121122151 Antibodies to such animal proteins reported in a few patients; effect on clinical response not fully elucidated.4045

Latex Sensitivity

Packaging components for some preparations (e.g., Recombinate) may contain natural latex proteins; take appropriate precautions if injection is handled by or administered to individuals with a history of natural latex sensitivity.1147148

General Precautions

Risk of Transmissible Agents

Since antihemophilic factor (recombinant) preparations are not prepared using pooled human plasma, they are associated with a decreased risk of transmission of human viruses compared with plasma-derived antihemophilic factor (human).3489144049525569737679110

Theoretical but remote risk of transmitting other viruses (e.g., those associated with mammalian cell cultures employed in manufacturing).404979106108110 No such transmission reported to date.79110

Laboratory Monitoring

Monitor for development of factor VIII inhibitors during treatment, prior to surgery, and when switching between different factor VIII preparations.12728556567749195122126 If expected plasma factor VIII levels are not attained or bleeding is not controlled with an expected dose, perfom appropriate laboratory test (Bethesda assay) to detect and measure concentrations of factor VIII inhibitors.1120121122 (See Development of Inhibitors to Antihemophilic Factor under Cautions.)

Sucrose Content

Helixate FS (250-, 500-, and 1000-unit vials) and Kogenate FS (250-, 500-, and 1000-unit vials) contain 28 mg of sucrose per vial, while Helixate FS (2000- and 3000-unit vials) and Kogenate FS (2000- and 3000-unit vials) contain 52 mg of sucrose.120121 The manufacturers state that IV administration of these injections will not affect blood glucose concentrations.120121

Specific Populations

Pregnancy

Lactation

Not known whether antihemophilic factor (recombinant) is distributed into human milk.1120121122151 Use only if clinically indicated.2120121

Pediatric Use

Helixate FS, Kogenate FS, Recombinate, ReFacto: Have been used in children of all ages without any unusual adverse effects.124547120121122 Helixate FS and Kogenate FS also indicated for routine prophylactic treatment in pediatric patients with no preexisting joint damage.120121

Xyntha: Has been evaluated in a small number of previously treated pediatric patients 12–16 years of age with hemophilia A; pharmacokinetic parameters in these patients appeared to be similar to those obtained in adults.151 A study in previously treated patients <6 years of age is ongoing.151

Clearance of factor VIII is higher in children than in adults, resulting in shorter half-life and lower recovery of factor VIII; consider these pharmacokinetic differences when selecting dosage or monitoring factor VIII levels in pediatric patients.120121122

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.2120121122151 Individualize dosage.2120121122151

Elimination

Metabolism

Elimination Route

Half-life

Special Populations

Compared with adults, children have higher clearance, lower recovery of factor VIII, and a shorter factor VIII half-life; more frequent or larger doses may be necessary to adjust for these pharmacokinetic differences.120121122

Stability

Storage

Parenteral

Powder for IV Infusion

Advate: 2–8°C (avoid freezing to prevent damage to the diluent vial).122 May store at room temperature ≤30°C up to 6 months; do not return drug to refrigerator after storage at room temperature.122 Do not use beyond expiration date.122 Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.122 Discard any unused portion of the drug.122

Helixate FS: 2–8°C (avoid freezing); may store at room temperature ≤25°C up to 3 months.121 Do not return to refrigerator after storage at room temperature.121 Do not use beyond expiration date.121 Protect from extreme exposure to light and store lyophilized powder in the carton prior to use.121 Use solution within 3 hours of reconstitution.121

Kogenate FS: 2–8°C (avoid freezing); may store at room temperature ≤25°C up to 3 months.120 Do not return to refrigerator after storage at room temperature.120 Do not use beyond expiration date.120 Protect from extreme exposure to light and store lyophilized powder in the carton prior to use.120 Use solution within 3 hours of reconstitution.120

Recombinate: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤30°C.1 Do not use beyond expiration date.1 Do not refrigerate after reconstitution; use solution within 3 hours of reconstitution.1

ReFacto: 2–8°C (avoid freezing to prevent damage to the diluent vial); may store at room temperature ≤25°C up to 3 months.2 Do not use beyond expiration date.2 Protect from extreme exposure to light.2 Use solution within 3 hours of reconstitution.2

Xyntha: 2–8°C; may store at room temperature ≤25°C up to 3 months.151 Do not return to refrigerator after storage at room temperature.151 Do not use beyond expiration date.151 May store prefilled diluent syringe at 2–25°C (avoid freezing to prevent damage).151 Protect from prolonged exposure to light.151 Use solution within 3 hours of reconstitution.151

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Formal compatibility studies have not been performed; manufacturer states antihemophilic factor (recombinant) should not be administered in the same tubing or container with other drugs.2134138151

Actions

Antihemophilic factor (recombinant) is structurally similar to and appears to produce the same pharmacologic effects as endogenous human blood coagulation factor VIII.13478910124049506977

Patients with hemophilia A have decreased levels of endogenous factor VIII or dysfunctional factor VIII, resulting in a hemorrhagic tendency and clinical manifestations such as bleeding into soft tissues, muscles, and weight-bearing joints.141223244169739596151 Therefore, replacement therapy with exogenous antihemophilic factor is necessary.151

Clinical severity and frequency of bleeding in patients with hemophilia A correlate with the degree of deficiency of factor VIII activity.2324417374 Patients with mild hemophilia A generally have >5% of normal activity, those with moderate disease generally have 1–5% of normal activity, and those with severe disease have <1% of normal activity.232495

Administration of antihemophilic factor (recombinant) to patients with hemophilia A results in increased plasma levels of factor VIII and temporarily corrects the coagulation defect in these patients.1259404755686973120121122151

Advice to Patients

Risk of developing inhibitors to factor VIII; importance of patients informing clinician if they experience a lack of clinical response to antihemophilic factor replacement therapy, which may be a sign of inhibitor development.12120121122151

131. Medical and Scientific Advisory Council (MASAC), National Hemophilia Foundation. MASAC recommendations regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors) (June 3, 2006). MASAC recommendation #167. From National Hemophilia Foundation website ().

142. World Federation of Hemophilia. Diagnosis and management of inhibitors to factors VIII and IX: an introductory discussion for physicians. 2004. From World Federation of Hemophilia website (). Accessed 2007 Sept 19.

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